delta5-20-keto-3:16:21-trihydroxy-pregnenes and esters thereof



A -20-KETO-3:lfifil-TRlHYDRoxY-PREGNENEs.

AND. ESTERS THEREOF Albert Wettstein, Basel, Charles Meystre, Arles'heim, and Walter Voser, Basel, Switzerland, assignors to- Ciba Pharmaceutical Products, Inc., Summit; NJ.

N0 Drawing. Application June 3,1954

ScriaLNc. 434,336

Glaims priority, application Switzerland June 12; 1953 3 Claims, (Cl. 2604- 397317)" This invention relates-to novel compounds of the-pregnane series and a processfor preparingthem.

It is known to prepare compounds ofthe suprarenal cortex hormone series by the introduction qr an acyloxy group into the 2l-position of ZQ-keto-pregnanes by means of metal acylates or aryliodoso acylatels (see for eample British Patents Nos. 502,474, 524,006 and 536,210 and French Patent No. 898,140). K

The present invention is concerned" with the manufacture of ZO-keto-compounds of the pregnane series which contain in each of the 3- and 16-positions a free or functionally converted hydroxylj or 0x0 group, in 2l -posi tion a free or substituted hydroxyl group, eg, an acyloxy group, for instance a lower alkanoyloxy group, and preferably a double.- bond extendingfrom the S-carbon atom toone of the carbon atoms 4' and 6. 1 These ZO-keto-pregnames are of especial value because they eitherexhibit the activity of suprarenal cortex hormones-and are useful for adrenal cortical insuffieiency, or as intermediates which can be converted intosuch hormones by known-methods.

The novel compounds are obtained by reacting-- with metal acylates such compounds ofthe pregnaneseries as contain in 3- and in 1-6-positiona free-or'functionally converted hydroxyl or 0x0 group, in- 20-position oxo group and in 2l-position at least one hydrogen atom, and optionally converting any functionally-converted hydroxyl or 0x0 groups to free hydroxy and oxo groups.

United States Patent As startingmaterials compounds ofthe' pregnaneser-ies are used, among Which are to be understood notonly the actual pregnane derivativesbut also any compounds which are stereoisomeric, for'example- 5-, l=4- or 17'- position, racemates, such as are obtained by=total synthesis and homologous compounds, as for example 4-methyl,

4:4-dimethyl-, 14-methyl-, 1'7-methyland ZI-methyl-derivatives and also 1-9-nor, l8:19-bisno'r-, C-norand D- homo-compounds. They may be saturated or unsaturated for example in 1-, 4-, 5'-, 9111-, 11- and/or'l4-position. They contain as substituents, in addition to the 20- of acetic acid, trimethyl aceticacid, propionic acid; 4--' methyl-S-acyloxy valeric acids, benzoic acid, b'enzyl carbonic acid, diphenylmethyl carbonic acid, methane sulfonic acid or p-toluene sulfonic' acid; As examples of functionally converted oxo groups there maybe especiallymentioned ketals including cyclic compounds, which are derived, for example, from ethylene, propylene or butylene glycols, enol derivatives, such as-enol-ethers, enol esters and enamines, for example of pyrrol-idine, and also hydrazones, for example semi-carbazonesl Errol derivativesof cam-unsaturated ketones, such as M-li-ketoncs,

Patented July as, 959

. 2 are lesssuitable, on account of the sensitive conjugated double bond system, for reaction-with metal acyl'ates. In

addition tothe substituents in the specified positions, the

starting materials can also contain further substituents, especiallyfree or substituted hydroxyl or 0x0 groups, epoxy groups or halogen atoms, for example in 2-, 4-, 51-, 6-, 7-, 11-, 12-, 14-, 15-, 17- and l9-position. Especially to the Zl-carbon atom to which at least one hydrogen atom is attached, there can also be attached in addition thereto, for example, a carboxyl, carbalkoxy or oxalyl group.

As metal acylates for the reaction there are particular- 13/ suitable lead tetraacylates, such as lead tetraacetate,

propionate, butyrates, valerates, trimethyl-acetate, un-

decylenate, benzoate, cyclopentyl-ipropionate or phenylpropionate. As solvents are usedespecially the acids corresponding to the acyl residues, such asacetic; acid, propionic, acid or valeric acid, often with an addition of the corresponding, acid anhydrides, such as acetic anhydri'de or butyric acid anhydride, and if desired also aimther inert, solvent or diluent, such ashexane, heptane, benzene or toluene. In general temperatures are usedin the neighborhood; of 70 C. In the presence of' sensitive Isubstituentgsuch as a free or acylated l-6-hydroxyl group,

andin order to avoid any reaction which may sometimes tend to take place to some extent in l7-position, the process can also be carried out at considerably lower temperatures, for example at room temperature, if desired in the presence ofsmall quantities of catalysts, such as acids or boron trifluoride.

As stated above, functionally converted hydroxylor oxo groups in the 21-acyloxy compounds of the pregnane series which are obtained, can be liberated or split off. For thispurpose the agents and conditions known per se can be used which are suitable according to the nature of the substitution. Thus, for example, alkoxy, aralkoxy, acyloxy, ketal, enol ether and enol ester groups may be split oil by means of acid or alkaline hydrolyzingor transesterifying agents. The relatively energetic reaction condition for the splitting ofi of the alkoxy and aralkoxy substituents render their use in this case of less advantage, on the other hand acyloxy groups and also the other specified substituents can be hydrolyzed by the gentle action of alkaline, acid or trans-esterifying agents, for example by bicarbonate solution or dilute mineral acids. 1 6-acyloxy groups, and also the free substituents in this position can also be easily split oil in this operation with the formation of a double bond. AralkoXy groups and corresponding carbonic acid esters. can in most cases be split off merely by careful hydrogenation, for example by means of palladium-calcium carbonate catalyst. They are therefore applied with advantage, for example in 16-position, if the splitting oil of the substituent, which takes place especially easily in this position with formation of a double bond, is required to. be avoided. Enamines can in general be split up merely by heating in an inert solvent, which limits their application in acylation in 2l -position. Hydrazones are advantageously split up with acid agents in the presence of carbonyl compounds such as pyroracemic acid. In the hydrolytic methods of splitting up mentioned above, in general also the 21-hydroxyl group and any hydroxyl or 0x0 group in lo-position are also liberated. Especially the former, or also, for example, a 16.-hydroxyl group, can subsequently be. esterified or etherified,

desired partially;

' For this purpose the customary reagents are used, for example acid chlorides or anhydrides or isopropenyl acylates, if desired only in approximately equivalent amounts'and under very mild reaction conditions. In this manner, for example, the residues of acetic acid, trimethyl acetic, acid, propionic acid, valeric. acids; cen- 3 anthic acid, undecylenic acid, benzoic acid, phenyl propionic acid, cyclopentyl propionic acid, of polycarboxylic acids, hydroxy-carboxylic acids, polyoxymethylene carboxylic acids or of inorganic acids can be introduced. In the case of ethers, especially those with carbohydrates, such as ribose, glucose, galactose, saccharose, maltose or lactose can be prepared.

In products obtained which contain a free 3-hydroxyl group, the latter can be converted into. an oxo group in the conventional manner by. the action of dehydrogenating agents. For this purpose there can be used, for example, chromic acid in glacial acetic acid, chromium salts in an acid medium, chromium trioxide-pyridine complex, permanganates, metal alcoholates or phe- -nolates in ketones, -N-bromacetamide, for example in .dioxane-wateror pyridine-tert.-butanol, hypohalides, heating with metals or metal oxides such as copper oxide and so on. An isolated double bond (for example in 5:6-position) can be intermediately protected by attachment of halogen or hydrogen halide or by conversion into an i-steroid. If an nip-double bond is present (for example in 4:5-position), manganese dioxide is also suitable for the oxidation. If in addition to the 3-hydroxyl group other free hydroxyl groups are present, for example in 11-, 12- or 16-position, these latter can either be simultaneously dehydrogenated or, by selection of suitable dehydrogenating agents, milder reaction conditions, calculated quantities of the reagents and shorter reaction periods, the reaction can also to someextent be carried out with retention of hydroxyl groups.

Finally, in reaction products with a free 3-oxo group, a double bond can be introduced in a-position thereto in the known manner. Such a process advantageously includes bromination, reaction with a hydrazine, such as semi-carbazide and splitting of the hydrazone by means of a carbonyl compound such as pyroracernic acid.

The invention also includes any process in which there is used as starting material a compound obtainable as intermediate product at any stage of the complete process, the remaining stages of the process being then carried -out.

The following examples illustrate the invention, the relation between parts by weight and parts by volume being the same as that between the gram and the cubic centimeter:

Example 1 10 parts by weight of A -16-methoxypregnene-3. 8-01- -20-one are dissolved in 300 parts by volume of glacial acetic acid and the solution diluted with 200 parts by volume of benzene. The resulting solution is treated with 13 parts by weight of lead tetra-acetate, gently heated until the lead tetra-acetate is consumed and poured into ice water. The suspension is extracted with an ether-chloroform mixture (4:1). The ether-chloroform solution is washed With dilute, ice cold bicarbonate solution and water, dried and evaporated under vacuum. The residue is chromatographed on 300 parts by weight of aluminum oxide with elution with benzene-pentane mixtures and then with benzene and with benzene-ether mixtures. The benzene-pentane eluates contain-"some A 35:21-diacetoxy-16-methoxy-pregnene-2O-one, whereas on evaporation of the benzeneand benzene-ether eluates A -21-acetoxy-16-methoxy-pregnene-3B-ol-20-one is obtained. I

1 part by Weight of the latter compound is dissolved in 20 parts by volume of toluene. The solution is treated with 9 parts by volume of cyclohexanone and 5 parts by volume of the mixture are distilled off again in a current of nitrogen. With continuous distilling ofl, there is introduced dropwise into the boiling solution, within 25 minutes, a solution of 0.3 part by weight of aluminum isopropylate in 5 parts by volume of toluene. After further distillation for 15 minutes, the cooled reaction mixture is treated with an aqueous Rochelle salt solution and evaporated under vacuum. The suspension obtained 4, is extracted with ethyl acetate and the extract washed with water, dried and evaporated. The residue is chromatographed on 30 parts by weight of aluminum oxide. The hexane-benzene and benzene eluates yield: A -21- acetoxy-l6-methoxy-pregnene-3-20-dione.

.For hydrolysis, 1 part by weight of the above described crude A -'3,B:2l-diacetoxy-l6-methoxy-pregnene- 20-one is dissolved in a dioxane-water mixture and the solution treated with, 1 part by weight of potassium carbonate dissolved in a little water and the whole allowed to stand for 24 hours at 20 C. in a nitrogen atmosphere. After the addition of water, the reaction mixture is extracted with ethyl acetate and the ethyl acetate solution washed with water, dried and evaporated. The residue contains the oily A -3flz2l-dihydroxy-l6- methoxy-pregnene-20-one, which can be partially acetylated in 21-position in the following manner:

1 part by weight of the crude A -3fl:21-dihydroxy-16- methoxy-pregnene-ZO one is dissolved in 5 parts by volume of dry pyridine. The solution is treated with 0.3 part by volume of acetic anhydride, left to stand for 20 hours at 20 C. and, after the addition of Water, evaporated under vacuum. The residue is chromatographed on aluminum oxide as described above. The benzeneand benzene-ether eluates yield A -2lacetoxy-16methoxy-pregnene-313-01-20-one.

Example 2 chloride are added. After 21 hours standing at room temperature, the whole is poured into ice water and the suspension extracted with an ether-chloroform mixture (4:1). The organic solution is Washed with dilute'ice cold sodium carbonate solution and water, dried and evaporated under vacuum. The residue is chromatographed on 300 parts by Weight of aluminum oxide. The pentane and benzene-pentane eluates are rejected. From the benzene and benzene-ether eluates there is obtained as main product A -16-diphenylmethoxy-21- acetoxy-pregnene-313-01-20-one.

To 1 part by weight of the crude 21-monoacetate in 10 parts by volume of pyridine there is added a solution of 1.5 parts by weight of chromium trioxide in 2 parts by volume of water and 5 parts by volume of pyridine and the whole is allowed to stand for 24 hours at 20 C. After the addition of water the oxidation mixture is extracted with ethyl acetate. tion is Washed with ice cold potassium bicarbonate solution, and water and dried. It contains the crude A -16- diphenylmethoxy-Zl-acetoxy-pregnene-3:20-dione which,

' without furthenpurification, is hydrogenated in 20 parts by volume of ethyl acetate. After the addition of 0.1 part by weight of palladium-calcium carbonate catalyst the mixture is shaken at 20 C. with hydrogen until 1 mol has been taken up. The catalyst is then filtered ofi with suction and the solution carefully evaporated under vacuum. The-light yellow residue contains A -21-ace- .toxy-pregnene-16-ol-3:20-dione which is recrystallized from aqueous acetone.

The crude Aj -16-diphenylmethoxy-2l-acetoxy-pregnene- 3:20-dione can also be further worked up as follows:

1 part by weight of this compound is dissolved in 20 parts by volume of dry benzene. The solution is treated .with 1 part by volume of glycol and 0.1 part by weight of p-toluene sulfonic acid and slowly distilled with continuous dropwise addition of dry benzene. After 1 hour the cooled solution is Y washed with water, dried and evaporated under vacuum. The A -16-diphenylmethoxy- 21-acetoxy-pregnene-3z20rdione-3-monoketal which results is dissolved in 20 parts by volume of ethyl acetate. The solution is treated with 0.1 part by weight of palladium-c'alciumcarbonate.catalyst and hydrogenated at.20.

The ethyl acetate solu-,

likewise obtained;

5 -C. until 1 mol of hydrogen has been taken up. The catalyst is. then filtered with suction and. the solution evaporated under vacuum. Theresidue contains A -21- acetoxy-pregnenaIdol-3:20+dione-3-monoketal. It is dissolved'in 20I arts by. volume oi'v acetone and the solu- "tion treated-with :1 part by weight'of p-toluene sulfonic acid and allowed. to stand for 24' hours at 20 C. The acetone is thenevaporated oif under vacuum and. the residue taken. up in ethyl acetate and the ethyl acetate solution=washed with water, dried and evaporated. In manner.- A -21acetoxypregnener16-olr3:20-dione is Example 3.

10 parts by weight of Ai3B-acetoxy-16-[4-methyl-5- 'aceto yFvalerylOxy-Pregnene-Z0+one (obtained by treatment of diosgenin acetate with acetic anhydride at about Isequentbenzene and benzene-ether eluates are evaporated together., The, residue contains A -16-[4-methyl-5'-acetoxy-valeryloxyI-Zlracetoxy-pregnene-3fl-ol-20-one.

1, part by weightof, the latter compound is dissolved in parts by volume by. pyridine and the solution treated with-1.5, parts by weight of chromium trioxide, dissolved 2 parts, by volume of Water and 5 parts by volume Q1 'PY T diue and allowed tostand for 24' hours. at 20 C. Theoxidationmixtm'e treatedwith water and taken up inethyl' acetate. The ethyl acetate solution is washed with ice cold dilute hydrochloric acid, water, dilute ice coldpotassium bicarbonate solution and water, dried and evaporated. The residue constitutes A '-16-[4"-methyl-5'- acetoxy-valeryloxy] -21 acetoxy-pregnene 3:20 dione.

This compound is dissolved ina mixture of dioxane and water and the solution treated with 0.75 part by weight of, potassium bicarbonate in a little water and allowed to stand for 48 hours at, a low temperature. The solution is now. pouredinto a large quantity of water and the "resulting product extracted by shaking with ethyl acetate. 'The, ethyl acetate solution is washed with water, dried and evaporated under vacuum. In this manner, A -16: 2l-dihydroxy-pregnenezZO-dione is obtained.

Examplc4 0.1 part by weight of A -3,8:lofi-diacetoxy-pregnene- 17a-ol-20-one is dissolvedin 5 parts by volume of glacial "acetic acid. The solution is treated with 0.13 part by weight of lead tetra-acetate and heated in a nitrogen atmosphere. For isolation of the reaction product the T reaction mixture is poured into water and extracted with an ether-chloroform; mixture (4:1): and the organic solutiojn; washed with-dilute ice cold sodium bicarbonate solu- -tion= and'water and evaporated to dryness. The residue is chromatographed' on- 5 parts by weight of aluminum oxide. From the benzene-ether eluates there is obtained M1 16B:zl-triacetoxy-pregnene-l'lu-ol-ZO-one, which after recrystallization from ether melts at 181-183 C.;'

The A 35:l-ofi diacetoxy-pregnene-l7a-ol-20-oneused "as starting material can be prepared with advantage as "follows:

' 05' part by weight of A -3p-acetoxy-16:17a-oxidopregnene-20 one is dissolved in 10 parts by volume of glacial acetic acid and after the addition of 1 part by j'volumedf a mixture of 10 p arts by volume of glacial *acetic acid: and'[ 2 5- parts by volume of concentrated sulagain. With benzene. The combmed benzene solutions arewashed withwater, sodium: bicarbonate solution and water, dried and evaporated, From the crude product resulting (0 .53.. part by weight) there is obtained by crystallization from methanol or benzene-hexane 031 part: by weight of A -3.13:l6f3-diacetoxy-pregnene-1-7-a-ol- 'V I v I 'Water,"'dried'- and'evaporated '-fur1c-ac1d,"them1xture is allowed tostand for 6 hours residue there are obtained by crystallization from a mixchloroform).

The same compound is also obtained from the free A115;l'lu-oxide-pregnene-3p-olr20-one by treatment for 9 hoursv with glacial acetic acid-sulfuric acid in the above-described manner; acetylation of the hydroxyl groupin 3-polsition taking? place at. the same time as the rupture of thezepoxide; ring.

-l7ot-ol-20.-one is. dissolved: in 8: parts by volume of: diroxane. and'treated with 007 part by weight of potassium: hydroxide in. 2. parts by volume of water.. After 25 standingv'for 1 7. hours. at room temperature, the clear colorless solution is poured. into, parts by volume: of water. In this Way 0.12 part by weight of a crystalline trihydroxy-compound is deposited. The pure substance,

after recrystallization from acetone or ethanol, melts at 235-237 0.; [a]n? =63' (in chloroform).

- Example 5 To a solution of 1 part by weight of M-lSB-acetoxypregnene-1-7bt-oL3:20-dione in 50 parts by volume of glacial acetic acid, 049 part by weight of lead tetraacetate is added and the mixture is gently heated until the lead tetra-acetate is consumed and then poured into icewater. The suspension is taken up in ethyl acetate and the solution washed with dilute ice cold sodium bicarbonate solution and water, dried and evaporated under vacuum. By chromatography over aluminum 'oxide" the A :21 diacetoxy pregnene 17o: ol- 3'z2Q-dione is obtained of melting point 167'-1-68 C. (ot =-l-99' in chloroform) For hydrolysis of the acetate groups, 0.26 part by Weight of this compound is dissolved in 0.6 part by volumeof methanol and a sodium methylate solution from 0.03" part by-weightofsodium and 2.2 parts by volume of methanol is addedu After 3 minutes 1 part by volume of a mixture of equal parts; by volume of water and methanol is added and after a further three minutes the Whole is acidified with 0.1 part by volume of The reaction mixture is then conof; water andi extracted with chloroform. From the "chloroform, extract after washing with water, sodium carbonatesolution and waterand drying, there. is obtained afterevaporation of the solvent, on addition of acetone- 0.18 part by weight of a crystallizate. By recrystallization from acetone .and isopropyl ether, a trihydroxy-compound' is obtained of melting point 225 227 Q. (a al-101 in chloroform-ethanol).

The starting material used above may be prepared as follows:

3 parts byweight of A -l6:17a-oxido-pregnene3z20- dione are dissolved in 60 parts by volume of glacial acetic acid and treated with 6 parts by volume of a mixture of- 10 parts by volume of glacial acetic acid [and 225 parts by volume of concentrated sulfuric acid.

Afters hours, the solution, which has a strong red fluorescence, is poured into 350 parts by volume of ice water, extractedwith benzene and the benzene extracts washed with water, sodium bicarbonate solution and From the oily yellow with suction.

'ture' of benzene'and hexane 1.83 parts by weight of crude A -l6p-acetoxy-pregnene-l7a-ol-3 :ZO-dione. recrystallization from benzene-hexane and from acetone,

After 'by volume of glacial acetic acid, the reaction mixture is concentrated to 5-7 parts by volume, treated with 70 parts by volume of water and the precipitate filtered The resulting crude product is taken up in the moist condition in chloroform, washed with N-sodium carbonate solution and water and dried and evaporated. From the 0.41 part by weight of solid 'crude product obtained there is produced by recrystallization from a mixture of hexane and acetone a pure dihydroxy compound of melting point 217-219 C.;

=+92 (in chloroform). The compound exhibits in the ultra-violet spectrum a strong absorption maximum at 239 my. (e=16,150).

Example 6 To a solution of 10 parts by weight of A -3p-formy1- oxy-l6aacetoxy-20-keto-pregnene in 500 parts by volume of a 4:1 mixture of glacial acetic acid and acetic .anhydride are added 13 parts by weight of lead tetraacetate and the Whole is gently heated until the lead tetra-acetate is consumed, after which the reaction mass is poured on to ice Water.

The suspension is extracted by agitation with a 4:1-mixture of ether and chloroform, the ether-chloroform solution then washed with an ice-cold dilute potassium bicarbonate solution and water, dried and evaporated under reduced pressure.

The residue is recrystallized from a mixture of ether and pentane to obtain the A -3fi-formyloxy-16m21-diacetoxy-20-keto-pregnene of melting point 180-182 C. and showing the specific rotation [oz] =24 (in chloroform). This compound rapidly and strongly reduces an alkaline solution of silver diammine.

A solution of 1 part by weight of A -3B-formy1oxy- 16a:2l-diacetoxy-20-keto-pregnene in 50 parts by volume 1 of dioxane is mixed at C. with a solution of 0.5 part by weight of potassium bicarbonate in 5 parts by volume.

of water and allowed to stand for 10 minutes. The solution is then neutralized with dilute acetic acid and evaporated to a considerable extent under reduced pressure. The residue is dissolved in ethyl acetate, the ethyl acetate solution washed with dilute potassium bicarbonate solution of 0.4 part by weight of bromine in 5 parts by volume of carbon tetrachloride. The excess of bromine is then eliminated under reduced pressure. To the solution of the dibromide there is then added at C. a solution of 0.18 part by weight of chromium trioxide in 95 parts by volume of glacial acetic acid and 5 parts by volume of water, and the whole is allowed to stand at 20 C. for 10 hours. The excess of chromic acid is decomposed with some sodium bisulfate solution, and the reaction mass is then concentrated under reduced pressure. The

resulting suspension is extracted with ethyl acetate.

tion and water, dried and evaporated. By recrystallizahours. water and evaporated under reduced pressure at 35 C.

8 While cooling with ice, the ethyl acetate solution is Washed with dilute hydrochloric acid, dilutefpotassium bicarbonate solution, and water, then dried and evaporated. The residue is dissolved in 40 parts by volume of acetone and the solution mixed with a solution of chromous chloride (prepared from 9 parts by weight of chromic chloride) and allowed to stand at 20 C. for 20 minutes. The reaction solution is treated with water, the acetone evaporated under reduced pressure the residue taken up in ether, the ethereal solution washed with water, dried and evaporated. The crude product so obtained is chromatographed over 30 parts by weight of alkali-free alumina. The fractions obtained with benzene and ether are combined and evaporated'underreduced pressure.

The residue is crystallized from mixtures of acetone and petroleum ether to obtain the A -3:20-diketo16u:21-di- .acetoxy-pregnene of melting point 150.5153 C.;

(in ethanol). This compound rapidly and strongly reduces a solution of silver diammine and shows at 240 mu (e max.=l6,400 in alcohol) a strong UV. absorption.

The two acetoxy groups can be hydrolyzed as follows: An enriched active cholinesterase fraction is mixed with parts by volume of a sterile, dilute aqueous sodium acetate solution. While stirring well at 30-37" C. there is added a solution of 1 part by weight of A -3z20- diketo-l6m:21-diacetoxy-pregnene in a little acetone and some toluene. The resulting suspension is stirred for 2-3 days at the same temperature, then extracted with ethyl acetate, the extract washed with dilute hydrochloric acid, dilute potassium bicarbonate solution and water, dried and evaporated under reduced pressure. The residue is chromatographed over 30 parts by weight of silica gel and from the evaporated ether-ethylacetate and glacial acetic acid eluates there is obtained after recrystallization from acetone and methanol the A -3s20-diketo-l6az2ldihydroxy-pregnene in the form of needles which melt at 203205 C.; [a] =+114.5 (in ethanol); max. 241

m e=16,300 (in ethanol).

. cent solution of acetic anhydride in dry benzene are-added and the whole is allowed to stand at 20 C. for 20 The reaction solution is then treated with some The residue is taken up in a mixture of ether and chloroform (4:1), the solution washed in the cold with dilute hydrochloric acid, dilute sodium bicarbonate solution and water, dried and evaporated. For purification, the residue is dissolved in benzene andchromatographed over 30 parts by weight of alkali-free alumnia. From the evaporated ether-ethyl acetate eluates some unchanged A -3:20-diket0-16a:Zl-dihydroxy-pregnene can 'be obtained. From the further ethyl acetate eluates the A -3:ZO-diketo-l6u-hydroxy-2l-acetoxy-pregnene is isolated. From mixtures of methanol and ether it crystallizes in the form of prisms which melt at 207209 C.

The A -3/3-formyloxy-16a-acetoxy-ZO-keto-pregnene can be obtained as follows:

1 part by weight of A -3 8-form-yloxy-16a-benzyloxy-20- keto-pregnene is dissolved in 100 parts by volume of alcohol and hydrogenated in the presence of a palladium on charcoal catalyst until 1 mol of hydrogen has been absorbed. After removal of the catalyst by filtration and evaporation of the solvent in vacuo the crude A 35- formyloxy-l6u-hydroxy-20 keto-pregnene is dissolved in 5 parts by volume of pyridine and5 parts by volume of acetic anhydride and the-solution is allowed to stand at room temperature for 20 hours. The reaction mixture is then poured-into water, extracted with' ether and the organic solution is washed with dilutehydrochloric acid, sodium carbonate solution and water. After evaporation of the ether the A -3fi-formyloxy-16u-acetoxy-20- keto-pregnene is obtained which after recrystallization, melts at 195197 C.; [a] =44 (in chloroform).

What is claimed is: 5

1. A process which comprises treating a A -3tl6ocdiacyloxy-ZO-keto-pregnane wherein the acyl radicals are derived from a member of the group consisting of formic acid and a lower alkyl carboxylic acid in the 3-position and a lower alkyl carboxylic acid in the 16-position, with lead tetracetate to produce the corresponding 21-acetoxypregnene.

2. A process which comprises treating a A -3:16Bdiacyloxy-l7a-hydroXy-2O keto-pregnene wherein the acyl radicals are derived from a member of the group consisting of formic acid and a lower alkyl carboxylic acid in the 3-position and a lower alkyl carboxylic acid in the 16-position, with lead tetracetate to produce the corresponding 21-acetoxy-pregnene.

3. A compound of the formula:

CH; CH;

in which R and R stand for lower alkyl carbonyl groups. so

References Cited in the file of this patent UNITED STATES PATENTS FOREIGN PATENTS Great Britain May 7,

OTHER REFERENCES Fuknshima: Jour. Am. Chem. Soc. 73, 196-201 (1951).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,897,219 July .28 1959 Albert Wettstein et al It is hereby certified that error appears in the -printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1 line 20, for "eample read example column '7, line '73, for "sodium bisulfate solution" read sodium bisulfite solutio. column 8, line 55, for "alumnia" read alumina Signed and sealed this 22nd day of March 1960.

(SEAL) Attest:

KARL H AXLINE ROBERT C. WATSON Attesting Officer Commissioner of Patents 

3. A COMPOUND OF THE FORMULA: 